There is still only limited information available on the genetic control of early embryonic development in mammals. The long-term objective of this application is to utilize new technologies of germ-line introduction of exogenous DNA to identify and mutate genes involved in controlling early cell lineage decisions in the mouse embryo. Such a combined mutational and molecular genetic analysis provides a powerful new approach to genetic analysis of development and will have considerable implications for understanding normal human embryonic development and the processes that lead to fetal wastage and developmental abnormalities. The specific aim of this proposal is to pursue three strategies aimed at identifying and mutating genes involved in early development. Aim 1: To continue to screen transgenic mouse strains for new developmental mutations, to characterize the mutations and clone the wild-type genes. Aim 2: To identify and possibly mutate new genes active in ES cells or gastrulation-stage embryos by lacZ "gene-reporter" techniques. Aim 3: To develop efficient techniques for homologous recombination in ES cells and mutate N-myc and Hox 2.1 by this means.